Validation Study of Genes with Hypermethylated Promoter Regions Associated with Prostate Cancer Recurrence

Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed. Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 x 10(-6)), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 x 10(-4)). DNA methylation profiles did not differ by recurrence status for the other genes. Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence. Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. (C)2014 AACR.